Intracellular aggregation of abnormal species of phosphorylated tau (protein tau) is a major pathologic feature of a family of neurodegenerative diseases collectively referred to as the tauopathies. Tau normally functions to stabilize microtubules in neurons; however, it pathologically aggregates more than 15 neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease. The most common tauopathy is Alzheimer's disease, in which paired helical filaments (PHFs) of mis-folded protein tau aggregates in neurofibrillary tangles, in dystrophic neuritis of senile plaques, and in cell processes in the neuropil. Abnormal accumulation of protein tau is closely linked with postsymptomatic progression in Alzheimer's disease. Abnormal accumulation of protein tau in the cytoplasm of neuronal and glial cells also represents major structural hallmarks in the pathology of Pick's disease, corticobasal degeneration and progressive supranuclear palsy.
At present, researchers on the development of therapeutics for tauopathies focus primarily on agents that prevent abnormal phosphorylation or aggregation of tau proteins. However, it has been discovered that while aggregation of hyperphosphorylated protein tau is visible evidence of tauopathies, these neurofibrillary tangles appear to be less toxic than soluble intermediates of protein tau. High levels of tau intermediates, particularly aberrant tau species failed to be cleared from cells, cause cognitive dysfunction in AD and tauopathies. Therefore, agents that degrade or destabilize tau intermediates, clear aberrant tau species from cells, or otherwise reduce intracellular tau levels, are promising therapeutics for AD and tauopathies.
Natural products chemistry has produced several effective AD therapy leads, including the amyloid aggregation inhibitor curcumin, isolated from tumeric, the microtubule stabilizer paclitaxel from the Pacific yew tree, and the Streptomyces-derived Hsp90 inhibitor geldanamymcin.
The Myrica plant belongs to the family of Myricaceae and is widely distributed throughout the world. Many Myrica species are edible and have been used in folk medicines. Myrica cerifera (also known as bayberry) is abundantly present in the Southeast and Central United States, and has been used for treatment of fevers, jaundice, ulcers, diarrhea, and dysentery. Myrica cerifera and its chemical constituent myricanol, however, have not been previously reported to play any role in reduction of levels of protein tau.